Bottom Line:
In addition, during childhood we found waves of inter-individual variability that are different for the four proteins and include a stage during early development (<1 year) when only Gephyrin has high inter-individual variability.We also found that pre- and post-synaptic protein balances develop quickly, suggesting that maturation of certain synaptic functions happens within the 1 year or 2 of life.Alignment of synaptic ages is important for age-appropriate targeting and effective translation of neuroplasticity therapies from the lab to the clinic.

ABSTRACTAlthough many potential neuroplasticity based therapies have been developed in the lab, few have translated into established clinical treatments for human neurologic or neuropsychiatric diseases. Animal models, especially of the visual system, have shaped our understanding of neuroplasticity by characterizing the mechanisms that promote neural changes and defining timing of the sensitive period. The lack of knowledge about development of synaptic plasticity mechanisms in human cortex, and about alignment of synaptic age between animals and humans, has limited translation of neuroplasticity therapies. In this study, we quantified expression of a set of highly conserved pre- and post-synaptic proteins (Synapsin, Synaptophysin, PSD-95, Gephyrin) and found that synaptic development in human primary visual cortex (V1) continues into late childhood. Indeed, this is many years longer than suggested by neuroanatomical studies and points to a prolonged sensitive period for plasticity in human sensory cortex. In addition, during childhood we found waves of inter-individual variability that are different for the four proteins and include a stage during early development (<1 year) when only Gephyrin has high inter-individual variability. We also found that pre- and post-synaptic protein balances develop quickly, suggesting that maturation of certain synaptic functions happens within the 1 year or 2 of life. A multidimensional analysis (principle component analysis) showed that most of the variance was captured by the sum of the four synaptic proteins. We used that sum to compare development of human and rat visual cortex and identified a simple linear equation that provides robust alignment of synaptic age between humans and rats. Alignment of synaptic ages is important for age-appropriate targeting and effective translation of neuroplasticity therapies from the lab to the clinic.

Figure 6: Principal component analysis. (A) The percent variance captured by each component of the SVD analysis of protein expression in human visual cortex. The first 2 principal components represent 84% of the SVD. (B) The influence of each protein on the first principal component was reflected by the relative amplitude in the basis vectors. (C) The influence of each protein on the second principal component was reflected by the relative amplitude in the basis vectors. (D) Significant correlations (colored cells) between the first 2 principal components and the combinations of proteins derived from the basis vectors. The color indicates the magnitude (represented by color intensity) and direction (green indicates positive, red indicates negative) of significant correlations (Bonferroni corrected, p < 0.0035).

Mentions:
The principal components represent a linear combination of the expression of the four proteins and the influence that each protein had on PCA1 or PCA2 was reflected in the relative amplitude of the basis vector (Figures 6B,C). Analyzing the basis vectors for PCA1 and PCA2 was an important, 2-step process, that we used to link the principal components with relevant biological mechanisms (Beston et al., 2010; Pinto et al., 2013). First, we computed the basis vectors; this provides insights regarding the biological mechanisms driving the data. The basis vectors for PCA 1 (Figure 6B) showed positive contributions from all four of the proteins (albeit a very small amount for Synaptophysin), indicating that PCA 1 is driven by the combined expression of the 4 proteins (synaptic protein expression). For PCA 2, the basis vectors showed opposite directions for the pre-synaptic markers (Synapsin and Synaptophysin), and opposite directions for the post-synaptic markers for excitatory and inhibitory synapses (PSD-95 and Gephyrin) (Figure 6C). The opposite directions for the pairs of proteins suggests that PCA 2 is linked with changes in the balance between the pre- and post-synaptic protein pairs.

Figure 6: Principal component analysis. (A) The percent variance captured by each component of the SVD analysis of protein expression in human visual cortex. The first 2 principal components represent 84% of the SVD. (B) The influence of each protein on the first principal component was reflected by the relative amplitude in the basis vectors. (C) The influence of each protein on the second principal component was reflected by the relative amplitude in the basis vectors. (D) Significant correlations (colored cells) between the first 2 principal components and the combinations of proteins derived from the basis vectors. The color indicates the magnitude (represented by color intensity) and direction (green indicates positive, red indicates negative) of significant correlations (Bonferroni corrected, p < 0.0035).

Mentions:
The principal components represent a linear combination of the expression of the four proteins and the influence that each protein had on PCA1 or PCA2 was reflected in the relative amplitude of the basis vector (Figures 6B,C). Analyzing the basis vectors for PCA1 and PCA2 was an important, 2-step process, that we used to link the principal components with relevant biological mechanisms (Beston et al., 2010; Pinto et al., 2013). First, we computed the basis vectors; this provides insights regarding the biological mechanisms driving the data. The basis vectors for PCA 1 (Figure 6B) showed positive contributions from all four of the proteins (albeit a very small amount for Synaptophysin), indicating that PCA 1 is driven by the combined expression of the 4 proteins (synaptic protein expression). For PCA 2, the basis vectors showed opposite directions for the pre-synaptic markers (Synapsin and Synaptophysin), and opposite directions for the post-synaptic markers for excitatory and inhibitory synapses (PSD-95 and Gephyrin) (Figure 6C). The opposite directions for the pairs of proteins suggests that PCA 2 is linked with changes in the balance between the pre- and post-synaptic protein pairs.

Bottom Line:
In addition, during childhood we found waves of inter-individual variability that are different for the four proteins and include a stage during early development (<1 year) when only Gephyrin has high inter-individual variability.We also found that pre- and post-synaptic protein balances develop quickly, suggesting that maturation of certain synaptic functions happens within the 1 year or 2 of life.Alignment of synaptic ages is important for age-appropriate targeting and effective translation of neuroplasticity therapies from the lab to the clinic.

ABSTRACTAlthough many potential neuroplasticity based therapies have been developed in the lab, few have translated into established clinical treatments for human neurologic or neuropsychiatric diseases. Animal models, especially of the visual system, have shaped our understanding of neuroplasticity by characterizing the mechanisms that promote neural changes and defining timing of the sensitive period. The lack of knowledge about development of synaptic plasticity mechanisms in human cortex, and about alignment of synaptic age between animals and humans, has limited translation of neuroplasticity therapies. In this study, we quantified expression of a set of highly conserved pre- and post-synaptic proteins (Synapsin, Synaptophysin, PSD-95, Gephyrin) and found that synaptic development in human primary visual cortex (V1) continues into late childhood. Indeed, this is many years longer than suggested by neuroanatomical studies and points to a prolonged sensitive period for plasticity in human sensory cortex. In addition, during childhood we found waves of inter-individual variability that are different for the four proteins and include a stage during early development (<1 year) when only Gephyrin has high inter-individual variability. We also found that pre- and post-synaptic protein balances develop quickly, suggesting that maturation of certain synaptic functions happens within the 1 year or 2 of life. A multidimensional analysis (principle component analysis) showed that most of the variance was captured by the sum of the four synaptic proteins. We used that sum to compare development of human and rat visual cortex and identified a simple linear equation that provides robust alignment of synaptic age between humans and rats. Alignment of synaptic ages is important for age-appropriate targeting and effective translation of neuroplasticity therapies from the lab to the clinic.